β-Catenin Deletion in Regional Neural Progenitors Leads to Congenital Hydrocephalus in Mice
β-Catenin Deletion in Regional Neural Progenitors Leads to Congenital Hydrocephalus in Mice
复制标题
区域神经祖细胞中的β-连环蛋白缺失导致小鼠先天性脑积水
DOI：
10.1007/s12264-021-00763-z
复制
发表时间：
2021-08-30
影响因子：
5.6
通讯作者：
Liu，Ling
中科院分区：
文献类型：
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作者：
Ma，Lin;Du，Yanhua;Liu，Ling
先天性脑积水是一种主要的神经系统疾病，发病率和死亡率很高;然而，其潜在的细胞和分子机制仍然很大程度上未知。反映胚胎和出生后脑积水的可复制动物模型也是有限的。在这里，我们描述了一个新的先天性脑积水小鼠模型，通过敲除β-连环蛋白在Nkx2.1表达的区域神经祖细胞。从胚胎第12.5天到成年，在基因敲除小鼠中始终观察到进行性脑室扩大和大脑扩大。转录组分析显示，在β-连环蛋白敲除后，心室区的祖细胞维持功能严重障碍，因此纤毛生物发生功能严重障碍。组织学分析还显示，在胚胎和出生后阶段的脑积水小鼠的腹侧和背侧端脑的异常神经元布局。因此，敲除区域神经祖细胞中的β-连环蛋白导致先天性脑积水，并为研究这种毁灭性疾病的病理变化和开发治疗干预提供了可重复的动物模型。
Congenital hydrocephalus is a major neurological disorder with high rates of morbidity and mortality; however, the underlying cellular and molecular mechanisms remain largely unknown. Reproducible animal models mirroring both embryonic and postnatal hydrocephalus are also limited. Here, we describe a new mouse model of congenital hydrocephalus through knockout of β-catenin inNkx2.1-expressing regional neural progenitors. Progressive ventriculomegaly and an enlarged brain were consistently observed in knockout mice from embryonic day 12.5 through to adulthood. Transcriptome profiling revealed severe dysfunctions in progenitor maintenance in the ventricular zone and therefore in cilium biogenesis after β-catenin knockout. Histological analyses also revealed an aberrant neuronal layout in both the ventral and dorsal telencephalon in hydrocephalic mice at both embryonic and postnatal stages. Thus, knockout of β-catenin in regional neural progenitors leads to congenital hydrocephalus and provides a reproducible animal model for studying pathological changes and developing therapeutic interventions for this devastating disease.